The entry of human immunodeficiency virus (HIV-1) into target cells is mediated by the viral envelope glycoproteins. The gp120 exterior envelope glycoprotein binds the host cell receptors, CD4 and chemokine receptors. Receptor binding triggers conformational changes in the envelope glycoproteins that lead to the gp41 transmembrane envelope glycoprotein fusing the viral and target cell membranes. The ability of the HIV-1 envelope glycoproteins to undergo conformational rearrangement is essential for their function in promoting virus entry, and also contributes to escape from neutralizing antibodies. The overall goal of this application is an understanding of the conformational states available to the HIV-1 envelope glycoproteins;such understanding is essential to any rational attempt to block virus entry by drugs or vaccine-induced antibodies. This application will pursue several approaches that, in conjunction with structural analyses conducted in parallel, will illuminate the dynamic interactions that occur in the HIV-1 envelope glycoprotein complex. The specific aims of this proposal are: 1) To investigate the nature and biological relevance of the conformational states sampled by the HIV-1 envelope glycoproteins;2) To investigate the role of the gp120 N-terminal disulfide-bonded loop, inner domain and bridging sheet in the conformational transitions induced by receptor binding;and 3) To investigate interactions of gp120 and gp41 that contribute to subunit stability within the HIV-1 envelope glycoprotein complex.